This invention pertains to the controlled delivery of pharmaceutical agents and methods, dosage forms and devices therefor. In particular, the invention is directed to methods, dosage forms and devices for the controlled delivery of phenoxyethyl-substituted 1,2,4-triazolones that are useful as pharmaceutical agents, such as antidepressants, for example, nefazodone and nefazodone hydrochloride.
Phenoxyethyl substituted-1,2,4-triazolones have been described as potent antidepressants in U.S. Pat. No. 4,338,317, which is incorporated herein by reference in its entirety. One of the most effective antidepressants in that group of compounds is nefazodone hydrochloride, sold under the trademark Serzone(copyright) by Bristol-Myers Squibb Co., and having the chemical name 2-[3-[4-(3-chlorophenyl)-piperazinyl]propyl]-5-ethyl-4-(2-phenoxyethyl)-2H-1,2,4-triazol-3(4H)-one hydrochloride. Nefazodone hydrochloride and related compounds in the foregoing class of compounds, while rapidly absorbed, may be subject to extensive metabolism, resulting in low and variable bioavailability. For example, peak plasma concentrations for nefazodone hydrochloride occur at about one hour after dosing using conventional immediate release formulations and the half-life of nefazodone hydrochloride is on the order of 2-4 hours. The low bioavailability and short half-life of the aforementioned compounds results in the need for multiple daily dosing or dosing at drug levels that are high enough to obtain the desired anti-depressant effect, both of which may result in the occurrence of undesirable side effects in particular individuals under certain circumstances.
The art is replete with descriptions of dosage forms for the controlled release of pharmaceutical agents. For example, U.S. Pat. No. 5,536,507 describes a three component pharmaceutical formulation that utilizes, inter alia, a pH sensitive polymer and optionally an osmotic agent that will swell in the higher pH regions of the lower portion of the small intestine and the large intestine to release drug in those environments. Additional components of the dosage form include a delayed release coating and an enteric coating to provide a dosage form that releases very little, if any, of the drug in the stomach, a relatively minimal amount in the small intestine and reportedly about 85% or more in the large intestine. Such a dosage form provides for a widely varying time-release of drug after administration that may not begin for 1-3 hours until the dosage form has passed from the stomach and an additional 3 hours or more for the dosage form to pass into the large intestine. While nefazodone is described generally as being an example of drugs that may be included in the formulation, no particular description of a formulation containing nefazodone is provided; nor is a formulation described that would provide a release profile for nefazodone and related compounds that optimally would be one of sustained release such that after administration drug would be released at a uniform rate over time. Furthermore, the type of release profile described in the patent may be less than satisfactory for the administration of antidepressants.
U.S. Pat. No. 5,169,638 describes a buoyant controlled release pharmaceutical powder formulation to be filled into capsules that uses a pH dependent polymer formed from alginic acid and hydroxypropylmethyl cellulose to release pharmaceuticals at a controlled rate. It appears from the disclosure that the capsule formulation was intended to mimic the characteristics of a tableted formulation. While, nefazodone is disclosed generally as being deliverable in accordance with method of the description, as is the case with U.S. Pat. No. 5,536,507 discussed above, no description is provided of a formulation that provides the uniform release characteristics of the dosage forms containing nefazodone and related compounds of the present invention.
Devices in which a drug composition is delivered as a slurry, suspension or solution from a small exit orifice by the action of an expandable layer are described in U.S. Pat. Nos. 5,633,011; 5,190,765; 5,252,338; 5,620,705; 4,931,285; 5,006,346; 5,024,842; and 5,160,743, which are incorporated herein by reference. Typical devices include an expandable push layer and a drug layer surrounded by a semipermeable membrane. In certain instances, the drug layer is provided with a subcoat to delay release of the drug composition to the envirnoment of use or to form an annealed coating in conjunction with the semipermeable membrane.
Devices in which a drug composition is delivered in a dry state from a large exit orifice by the action of an expandable layer are described in U.S. Pat. Nos. 4,892,778, 4,915,949 and 4,940,465. Those references describe a dispenser for delivering a beneficial agent to an environment of use that includes a semipermeable wall containing a layer of expandable material that pushes a dry drug layer out of the compartment formed by the wall. The exit orifice in the device is substantially the same diameter as the inner diameter of the compartment formed by the wall.
U.S. Pat. No. 5,126,142, which is incorporated herein by reference, describes a device for delivering an ionophore to livestock that includes a semipermeable housing in which a composition containing the ionophore and a carrier and an expandable hydrophilic layer is located, along with an additional element that imparts sufficient density to the device to retain it in the rumen-reticular sac of a ruminant animal. The ionophore and carrier are present in a dry state during storage and the composition changes to a dispensable, fluid-like state when it is in contact with the fluid environment of use. A number of different exit arrangements are described, including a plurality of holes in the end of the device and a single exit of varying diameter to control the amount of drug released per unit time due to diffusion and osmotic pumping.
While dosage forms delivering the drug composition to the environment of use in the dry state may provide suitable release of drug over a prolonged period of time, the exposure of the drug layer to the environment of use may result in agitation-dependent release of drug that in some circumstances is difficult to control. Accordingly, it may be advantageous to release the drug as a slurry or suspension that may be metered by control of rate of expansion of the push layer and the size of the exit orifice in the dosage form as in accordance with this invention.
Although a variety of sustained release dosage forms for delivering certain drugs exhibiting short half-life may be known, not every drug may be suitably delivered from those dosage forms because of solubility, metabolic processes, absorption and other physical, chemical and physiological parameters that may be unique to the drug and the mode of delivery.
An aspect of delivery of the antidepressants described herein is that the administration of high dosages of drug may require drug loading in the compositions and dosage forms being administered in the range of 20% to 90% of the overall weight of the composition or dosage form. Such loading requirements may present problems in formulating compositions and fabricating dosage forms and devices that are suitable for oral administration and can be swallowed without undue difficulty. Loading requirements may present problems when formulating dosage forms that are to be administered a limited number of times per day, such as for once-a-day dosing, with a goal of uniform release of active agent over a prolonged period of time.
There remains a need for effective dosing methods, dosage forms and devices that will permit the controlled release of the aforementioned compounds over a prolonged period of time to reduce the amount of the active agent that the patient is exposed to at any particular time and to increase the time between dosing, preferably to obtain a once-a-day dosing regimen.
In one aspect, the invention comprises a sustained release dosage form adapted to deliver a suspension or slurry and release over a prolonged period of time at a uniform rate of release a compound of the following structural formula: 
or a pharmaceutically acceptable acid addition salt thereof, wherein R is halogen. Preferably the compound is 2-[3-[4-(3-chlorophenyl)-piperazinyl]propyl]-5-ethyl-4-(2-phenoxyethyl)-2H-1,2,4-triazol-3(4H)-one or 2-[3-[4-(3-chlorophenyl)-piperazinyl]propyl]-5-ethyl-4-(2-phenoxyethyl)-2H-1,2,4-triazol-3(4H)-one hydrochloride and the prolonged period of time is six hours or greater.
In another aspect, the invention comprises a dosage form comprising a compound of the following structural formula: 
or a pharmaceutically acceptable acid addition salt thereof, wherein R is halogen, adapted to deliver a suspension or slurry of the compound and release the compound over a prolonged period of time at a uniform rate of release of at least 3 mg/hr. Preferably, the compound is nefazodone or nefazodone hydrochloride and the prolonged period of time is six hours or greater.
In yet another aspect, the invention comprises a method of treating a condition in a subject responsive to administration of a compound of the following structural formula: 
or a pharmaceutically acceptable acid addition salt thereof, wherein R is halogen, which comprises orally administering to the subject a dosage form adapted to release a suspension or a slurry of the compound at a uniform rate of release over a prolonged period of time. Preferably, the compound is 2-[3-[4-(3-chlorophenyl)-piperazinyl]propyl]-5-ethyl-4-(2-phenoxyethyl)-2H-1,2,4-triazol-3(4H)-one or 2-[3-[4-(3-chlorophenyl)-piperazinyl]propyl]-5-ethyl-4-(2-phenoxyethyl)-2H-1,2,4-triazol-3(4H)-one hydrochloride, and the dosage form comprises an osmotic material and between 50 and 1200 mg of the compound. Most preferably, the dosage form is administered orally, once-a-day.
In still another aspect, the invention comprises a dosage form comprising a wall defining a compartment, the wall having an exit orifice formed or formable therein and at least a portion of the wall being semipermeable; an expandable layer located within the compartment remote from the exit orifice and in fluid communication with the semipermeable portion of the wall; and a drug layer located within the compartment adjacent the exit orifice, the drug layer comprising a compound of the following structural formula: 
or a pharmaceutically acceptable acid addition salt thereof, wherein R is halogen, wherein the drug layer is adapted to form a suspension or a slurry of the compound in the environment of use. Preferably the compound is 2-[3-[4-(3-chlorophenyl)-piperazinyl]propyl]-5-ethyl-4-(2-phenoxyethyl)-2H-1,2,4-triazol-3(4H)-one or 2-[3-[4-(3-chlorophenyl)-piperazinyl]propyl]-5-ethyl-4-(2-phenoxyethyl)-2H-1,2,4-triazol-3(4H)-one hydrochloride. The dosage form may optionally comprise a flow-promoting layer between the wall and the drug layer.
In another aspect, the invention comprises a method of treating a condition responsive to administration of a compound having the following structural formula: 
or a pharmaceutically acceptable acid addition salt thereof, wherein R is halogen, which comprises administering a slurry or suspension of the compound to provide a steady state plasma concentration of the compound of between 5 ng/ml and 2500 ng/ml with the proviso that during the 24 hour period after administration of the dosage form the quotient formed by [Cmax-Cmin]/Cmin is 3 or less. Preferably the compound is 2-[3-[4(3-chlorophenyl)-piperazinyl]propyl]-5-ethyl-4-(2-phenoxyethyl)-2H-1,2,4-triazol-3(4H)-one or 2-[3-[4(3-chlorophenyl)-piperazinyl]propyl]-5-ethyl-4-(2-phenoxyethyl)-2H-1,2,4-triazol-3(4H)-one hydrochloride.